Pyrimidino-dibenzo-azepine,-oxazepine,-thiazepine and diazepine derivatives

ABSTRACT

Compounds of the formula:   IN WHICH X represents oxygen, sulphur, the group NR4 or the group -CR5R6, r and s stand for an integer from 0-4, R1 and R2 represent halogen, hydroxy, an alkyl or alkoxy group with 1-6 carbon atoms, a trifluoromethyl group or an acyloxy group with 1-8 carbon atoms, R3 means hydrogen, an alkyl group with 1-6 carbon atoms, an aralkyl group with 7-10 carbon atoms or an aryl group, and R4, R5 and R6 stand for hydrogen or an alkyl group with 1-6 carbon atoms, AS WELL AS THE ACID ADDITION SALTS AND QUATERNARY AMMONIUM COMPOUNDS THEREOF. These compounds exert a potent antidepressive and anxiolytic activity.

United States Patent 1191 van der Burg 1 1 PYRlMlDlNO-DlBENZO-AZEPINE,-

OXAZEPlNE,-THIAZEPINE AND DIAZEPINE DERIVATIVES [75] Inventor: Willem Jacob van der Burg, Heesch,

Netherlands [73] Assignee'. Akzona Incorporated, Asheville,

122] Filed: Sept. 7, 1973 21 Appl. No; 396,251

[30] Foreign Application Priority Data Sept. 23, 1972 Netherlands 7212915 [52] 1.1.8. Cl... 260/251 A; 260/239 D; 260/239 DD;

260/2564 F; 424/251 [51] Int. Cl. C07D 471/04 [58] Field of Search 260/251 A, 2564 F [56] References Cited UNITED STATES PATENTS 3,470,181 9/1969 Wei et a1. 260/251 Primary ExaminerRichard .1, Ga11agher Assistant Examiner-Raymond V. Rush Attorney, Agent, or Firm-Francis W. Young; Philip M. Pippenger; Hugo E. Weisberger July 1,1975

[57] ABSTRACT Compounds of the formula:

in which X represents oxygen, sulphur, the group NR or the group .5R6,

3 Claims, N0 Drawings 1 2 PYRIMIDINO-DIBENZO-AZEPlNE.-OXAZEPINE,- The starting substance ll is cyclisized by means of a THIAZEPINE AND DIAZEPINE DERIVATIVES condensation with a reagent of the formula:

The present invention relates to novel biologically active pyrimidino derivatives. More particularly it relates to heXahydro-pyrimidino-dibenzo-azepines and 5 r A 1 7 tetrahydro-pyrimidino-dibenzo-oxazepines, -thiazepines and -diazepines. it a From the British Pat. No. l.229.252 compounds are known differing from the present compounds in that they contain a piperazine instead of a pyrimidino ring. in which These known piperazine derivatives possess potent an- Y represents hydrogen 2 Oxygen or Sulphur and tihistamine and antiserotonine activity. and 2 represents the 51mm or diffelehh reactive Surprisingly it has now been found that the present leaving p or y be togelher bivalent pyrimidino derivatives f the general f l active group, that can be eliminated together with IS the hydrogen atoms attached to both nitrogen atoms of the diamine 11. so forming a compound of v I the formula: QC

2O H d 3 n h- H I't A L! in which 75 n r and .i stand for an integer from 0-4,

R and R- represent hydroxy. halogen. alkyl or alkoxy with 1-6 carbon atoms. acyloxy with 1-8 carbon atoms. or a trifluoromethyl group,

R hydrogen, an alkyl group with 1-6 carbon atoms.

an aralkyl group with 7-l0 carbon atoms or an aryl in which X, Y. Q. R,. R R rand A have the aforesaid meanings.

in general, the groups 2 and 2 may represent halogen. a substituted or unsubstituted amino group. a free. etherified or esterified hydroxy or mercapto group or group Z and Z together may represent sulphur or oxygen. X: i sulphgir the guoup or the group If Y represents hydrogen H), Z and Z stand preferabl for halogen or hydroxy groups. Reagents III hydrogen or u lower "ukyl group F6 belonging to this type of compounds are. for example. Carbon moms methylenechloride. methylenebromide or methylene as well as the pharmaceutically acceptable acid addidiol formaldehyde Solution in water or a Water Com tion salts and pharmaceutically acceptable quaternary mining solvent). ammonium compouljds thereof have a completely If Y represents oxygen or sulphur the most suitable ferem pharmacological profile The compounds 4O moieties for Z, and Z are halogen. substituted or ancording to this invention snow. fully contrary to the substituted amino groups, an etherified or compounds described in the said British patent. a posiphonylated hydroxy or mercapto group or Z1 and Z2 tive effect in the reserpine antagonism test. which together are sulphur (in combination with Y sulmeans that h uml-qepressanf t F phur). Suitable reagents lll belonging to this type of whereas the antihistamine and antl-serotonme activity compounds are for example phosgene, thiophosgene the P compounds cnflsfderaply lowered in haloformic esters such as ethylchloroformate. esters of comparison Tong antihistamine Q carbonic acid such as dimethylor diethylcarbonate. tiserotonine activity of the compounds descrlbed in the urea and urea derivatives such as thiourea or N'- British P bonyl-di-imidazole. and carbondisulphide.

The Compwnds According to'the invention Q be Preferably methylenehalide or formaldehyde (in wa- P p y y method Commonly used for this type ter) is used as the reagent Ill in the present condensahf P y however P p most tion reaction if the starting compound II does not conveniently starting from a substance with the general mi a k m group (Q H because they yield the formula: sired final product according to the invention in a direct way.

/ a x If a reagent according to the formula III. in which Y a I I a i l why 7 represents oxygen or sulphur and/or a starting com- -,/*t-.-- &s pound ll. in which Q stands for oxygen is (are) used,

" d the resulting compound must be reduced additionally 4 to obtain the desired final product. For such a reduce tion any suitable reducing agent can be used. for example. metal hydrides such as sodium hydride. lithium aluminium hydride or diborane. Said reduction can also be or an acid addition salt thereof. in which preformed catalytically by hydrogenation in the pres- X. R, R R1,. r and s have the meanings indicated ence of a metal or a metal compound.

previously d If Z, and/or 2 represent halogen. an agent capable 0 means hydrogen (H or oxygen. of eliminating the hydrogenhalide formed during the condensation reaction. such as pyridine. triethylamine. etc.. is usually added to the reaction mixture.

The condensation reaction can be performed in any suitable solvent. Where methylenehalide is used as the reagent lII. special preference is given to an aprotic polar solvent. such as dimethylsulfoxide. sulfolane or acetonitril. it is also possible. however. to perform the condensation exclusively in the reagent lll. so ina(additional) solvent. in certain cases. e.g. in the absence of any (additional) urea is used as the reagent ill. the condensation can be carried out in a melt.

The starting substances of formula II required in the present invention can be prepared by any process described for similar compounds. Thus. for example. the compound o-chloro-methyl-l lH-dibenzolb.e]azepinc can be reacted with a cyanate. for example sodiumcyanate. The resulting nitrile may then either be reduced to the corresponding amino compound optionally followed by introduction of the desired R;.-group. so yield- The substituent 1 R1.) at the N nitrogen atom can also be obtained after the condensation reaction by alkylating or aralkylating the unsubstituted nitrogen atom (R H) or by acylating the unsubstituted nitrogen atom followed by a reduction of the carbonyl moiety of the N-acyl compound thus obtained.

it is also quite obvious and well-known in the art to convert the aklylor aralkyl substituted N-nitrogen atom (of formula I) into the unsubstituted nitrogen. for

l example by heating with chloroformic ester. followed by hydrolysis of the compound thus obtained.

The compounds according to the present invention have as already mentioned a completely different pharmacological profile with respect to the related known piperazinederivatives as described in the British Pat. No. 1.229.252.

The present compounds show a positive effect in the reserpine-antagonism test and in the reserpine-reversal test. which means that they can be applied as antideing a compound ll ith Q H2. or be hydr lysed and 20 pressive agents. The present compounds possess more optionally followed by introduction of the R;.-group. so generally strong CNS stimulatroy properties which toforming a compound H in which oxygen. gether with their effects against agression means that The acid addition salts of the compounds according the compounds of the present invention have also poto the invention are prepared in conventional manner tent anxioly tic properties. by reacting the free base with a pharmaceutically ach They can be administered both orally and parenterceptable acid such as hydrochloric acid. hydrobromic ally. preferably in a dosage of between 0.0l and mg acid or hydroiodic acid. phosphoric acid. acetic acid. P g Y Weight. Mixed with Suitable auxiliaries he propionic acid. glycollic acid. maleic acid. malonic Compounds can be compressed into said dosage units. aicd. succinic acid. tartaric acid. citric acid. ascorbic Such 115 P filbleiS n Coated lets. They Can also id, li li acid or b i id, be processed into capsules. mixed with auxiliaries ifde- The pharmaceutically acceptable quaternary ammo- Y means of Suitable liquids the compounds I can nium compounds, in particular the lower l4C) alkyl f applied injection Preparations in the form of Soluquaternary ammonium compounds. are obtained by ret10n5- emulsiflns Suspensions acting the compounds of the general formula I with an P which are Preferably used in Present alkyl halide. for example methyl iodide or methyl bromide.

From the above general formula i it appears that the y 234. l l y -py l 3 compounds according to the invention possess an aldebenzo-[c.f}azepine. asymmetrical carbon. Consequently optical antipodes 40 B-methyl-l.3.4.l4b-tetrahydro-2H-pyrimidino[3.4- are possible. also forming part of this invention. Said d]dibenz0-[b.fl(l.4)oxazepine, optical antipodes can be isolated from the racemic mix- 3.1 l-dimethyl-l.3.4.14b-tetrahydro-2H-pyrimidino tue in a conventional manner. It is also possible to rel l -l l( )0 P l. solve the racemic starting product ll into its optical an- -m hylrifl rornethyl-i .3.4.l4b-tetrahydro-2H tipodes and to perform the condensation reaction after pyrimi in l l i nz l l( l Pin6. that. or to resolve an intermediate product obtained y Y during the aforesaid synthesis of the compounds I. py 'l l l l( P it is of course possible to introduce or modify the y Y y substituents at one or both phenyl nuclei after the conpy l l l li ldensation reaction. Thus. for example. a hydroxy group present can be acylated or converted into an alkoxy The following examples serve to illustrate the invengroup. an amino group into a halogen group. a metion further. In the examples the following nomenclathyoxy group into a hydroxy group. etc. ture and numbering have been used:

B-methyl- I 23.4. I 0.1 4b-hexahydro-pyrimidinol 3.4- aldibenzo [c.f]azepine.fumarate Two grams of the diamine 6-methylaminoethyl-5,6- dihydrol lH-dibenzo[b.e]azepine (melting point I24- l27C) are dissolved in 25 ml of 96% ethanol. Then l0 ml of a 35% formaldehyde solution in water are added. after which the mixture is left to stand for 30 minutes.

Then this mixture is poured into 250 ml of water. after Rf in henzenemiethanol (9:1 0.48 on SiO EXAMPLE [I 1.2.3.4. l 0. l 4b-hexahydro-pyrimidinol34-a dibenzolcjl-azepine and HCL salt ln the same manner as described in example I 2 g of the diamine 6aminoethyl-5,6-dihydro-l lH-dibenzoIb .el-azepine (m.p. l52l53C) are dissolved in 10 ml ofa 35% formaldehyde solution in water. The solution is set aside at 20C'for 30 minutes, after which it is poured out into 250 ml of water and extracted 3x with methylene chloride, washed with water and evaporated by means of a film evaporator. The remaining oil is purified by means of a chromatographic column (the solvent mixture is benzenermethanol (9:I)). Rf in benzenermethanol (822) 0.50 on $0,.

Then the resulting oil is dissolved in as little HCL- containing alcohol as possible. after which the solution is cooled down. The crystals formed are filtered off.

Melting point: 2 l2-2 l 7C.

EXAMPLE [I] Resolution of: 3-methyl-l .2.3.4. 1 0. I 4b-hexahydro-pyrimidinol 3.4- a l-dibenzo[c.fl-azepine Racemic 3-methyl- I 2.3.4.10. I 4b-hexahydropyrimidine-l3.4-al-dibenzolc.f]-azepine (oil from example l. l.7 g) is dissolved in 20 ml of ethanol. To this solution a solution of 1.3 g of (+l-dibenzoyl tartaric acid. also in 20 ml of ethanol. is added. After 4 days the precipitate formed is filtered and washed with ethanol. Then the precipitate is treated with an lN sodium hydroxide solution and ether. The ether layer is separated out. washed with water. dried over sodium sulphate and evaporated. Of the remaining oil the rotation is determined.

la P" 437 0.l in ethanol).

The treatment of the oil described above is repeated twice to obtain a compound of 1o 1 ----496" (c 0.l in ethanol). Melting point: l0l"l03C.

ln the same manner the rotating isomer is obtained by reacting the racemate with ()-dibenzoyl tartaric acid. lmlF" +492 (1' 0.! in methanol).

EXAMPLE lV By the process described in example I the following substances are prepared:

3.7-dimethyl-l .3.4. l 4b-tetrahydro-2H- pyrimidinol 3.4-d |-dibenzo[b.f]( l .4)oxazepine.- maleate. melting point: l64"l66C;

6. 3. l3-dimethyll 3.4. 4b-tetrahydro-2H- pyrimidinol 3.4-d l-dibenzol b.f]( l.4 )oxazepine.

EXAMPLE v IO-dimethyl-l .2.3.4. I 0. l 4b-hexahydropyrimidinol 3.4-d]dibenzo[b.f]( l .4 )diazepine derivatives One gram of the diamine 5 methyl-l lmethylaminoethyll 0.l l-dihydro5H-dibenzo[ b- .e]( l .4 )diazepine is dissolved in ml of 90% ethanol. To this solution 5 ml of a formaldehyde solution in water is added. The mixture isleft to stand for lhour at room temperature and after that poured out into l 50 ml of water. Extraction with methylene chloride and evaporation of this CH Cl -phase gives the free base as an oil.

Rf in methanol 0.35 on SiO- lodomethylate: melting point 2l22l5C.

Starting from the diamine: Z-methoxy-S-methyl-l lmethyl-aminoethyll 0,1 ldihydro-5H- dibenzo[b.e](l ,4)diazepine (melting point HBr-salt 207208) the free base 3.l0-dimethyl-l3-methoxyl,2.3.4. l 4b-hexahydro-pyrimidinol 3.4d dibenzolb.f]( l.4)diazepine is obtained as an oil in the same way. Melting point picrate l03-l08C.

Rf in methanol 0.45 on SiO- A quantity of this substance is the converted into the fumarate (see example I). melting point 2l0-2l5C. another quantity into the iodomethylate (melting point: 204207C) by means of CH EXAMPLE VI By the same process as described in example II are prepared: 1. 1.3.4. 1 4b-tetrahydro-2H-pyrimidino[ 3.4-

d]dibenzolb.f]( l.4)oxazepine.HC'l; melting point l99-204C. RF in methanol 0.90 on SiO 7-trifluoromethyl l .3.4. l 4b-tetrahydro-2H- pyrimidino[3.4-d ldibenzol b.f]( [.4 )thiazepine; melting point l23-l26C. RF in benzenezethyl acetate (7:3) 0.25 on SiO-;.

3. l0-methyl-l3-rnethoxy-l.2.3.4.l0.l4b-hexahydropyrimidinol3.4-d]dibenz0lb.f]( 1.4)diazepine (oil). Rf in methanol 0.5l on SiO- Rf in ethyl acetate 0.40 on SiO 4. l l-methyll .3.4. l 4b-tetrahydro-ZH-pyrimidinol3.4-

d l-dibenzol b.f]( l.4 )oxazepine.maleate; melting point l77l79C.

5. B-methoxy-l .3 .4. l 4b-tetrahydro-2H- pyrimidinol 3.4-d]dibenzolb.fl( l .4 )oxazepine (oil). Rf in methanol 0.45 on SiO:.

6. S-hydroxyl .3.4. l 4b-tetrahydro-2H-pyrimidinol3.4- d]dibenzo[b.fl( l .4)oxazepine. Rf in methanol 0.25 on SiO 7. 7-methyll .3 .4. l 4b-tetrahydro-ZH-pyrimidinoI 3.4-

d]dibenzo[b.f]( l .4)oxazepine.maleate; melting point l64l66C.

8. 3.7-dimethyll 3-chloro-l .3.4. I 4b-tetrahydro-2H- pyrimidino[3.4-dldibenzo[b.f](1.4)oxazepine (oil).

EXAMPLE Vll 3-ethyl-l 2.3.4. 1 0. l 4b-hexahydro-pyrimidino[ 3.4- a]dibenzo[c.f]azepine.HCl (direct route) In the same manner as described in example l the diamine 6-ethylaminoethyl-5.fi-dihydro-l l H- dibehzolbelazepine is dissolved in ethanol. The solution is treated with a formaldehyde solution and the mixture extracted with methylene chloride. The methylene chloride extracts are washed and dried. after which the resulting residue is dissolved in HClcontaining ethanol. The resulting crystals are recrystallized from ethanol.

Yield 72%; melting point: l98-200C. Rf in ethylacetate 0.l5 on SiO In the same manner the corresponding 3-benzyl and 3-phenyl derivatives are prepared.

EXAMPLE Vlll 3-ethyl-l .2.3.4. I 0, l 4b-hexahydro-pyrimidino[ 3.4- a ]dibenzo[c.f]azepine.HCl (indirect route) l.3 g of l2.3.4.l(l.l4b-hexahydro-pyrimidinol3.4- a|dibenzo[c.f]azepine (example ll) are acylated in benzene by means of 2 ml of acetic anhydride.

After 30 minutes' stirring at C. the solution is evaporated and the residue purified by means of column chromatography (solvent ethylacetate; column silicagel).

The resulting oil. the N-acetyl derivative of the starting substance. has an Rf value of 0.48 in ethylacetate.

Of this oil 0.8 g is dissolvedin l0 ml of tetrahydro furan and gently added to a suspension of 0.5 g of LiAlH. in ml of tetrahydrofuran. Then the mixture is refluxed for one hour. after which it is cooled down. Then 2 ml of water are added.

The precipitate formed is filtered off and the filtrate evaporated. The resulting residue is dissolved in HClcontaining alcohol. after which the product is allowed to crystallise out.

Yield 0.5 g. Melting point: 196-200C. Rf in ethylacetate 0. l6 on SiO A mixture of the substances (Ii-ethyl derivatives) prepared in examples VI! and VIII melts at l96200C.

EXAMPLE IX 3-methyl-l .2.3.4. 1 0. l 4b-hexahydro-pyrimidino[ 3.4- a]dibenzo [c.flazepine A mixture of 2.4 g of 6-methylaminoethyl-5.6- dihydro-l lH-dibenzolbelazepine. 10 ml methylene chloride. 2 ml oftriethylamine (TEA) and 10 ml of dimethylsulfoxide (DMSO) is refluxed for 5 hours. The excess of methylene chloride. TEA and a large quantity of the DMSO are distilled off in vacuum. The remaining liquid is diluted with water and then extracted with ether. The etherial solution is then washed with water. dried and evaporated to dryness.

The residue is treated with fumaric acid in ethanol. Melting point fumarate: l88-l9lC.

EXAMPLE X In the same manner as described in example IX are prepared:

point:

EXAMPLE x1 I .2.3410. l4b-hexahydropyrimidinol3.4- a ]dibenzolc.f]azepine.HCl

A. A solution of L2 g ofthiophosgene in l0 ml oftoluene is gently added. at 0C. to a solution of 2.4 g of 6-aminoethyl-5.o-dihydro-l lH-dibenzo[b.e]azepine in 20 ml of toluene to which 5 ml of pyridine have been added. The reaction mixture is left to stand for 1 hour and after that 20 ml of water are added. The mixture is stirred vigorously. after which the water layer is separated trom the toluene layer. The toluene phase is washed with water. then with 0.2 M sulphuric acid and finally with water.

The toluene solution is then dried and evaporated to dryness. The residue is recrystallized from ethanol (2.2

Melting point l2.3.4.10.l4b-hexahydro-4-thionepyrimidino[3.4-a]dibenzo[c.f]azepine: l96l98C.

8. Two grams of the substance obtained in A are added to a suspension of4 g of LiAlH. in 50 ml of dioxane. The mixture is refluxed for 1.5 hours. After being cooled down the mixture is added dropwise to 15 ml of water. The mixture is filtered and the filtrate evaporated to dryness in vacuum. The residue is dissolved in hydrochloric acid-containing alcohol. after which the solution is cooled down to obtain a precipitate. Melting point: 2l32I7C. Yield 0.9 g.

C. The same compound is obtained in two steps. if. instead of thiophosgene in toluene. carbondisulphide is used as reagent and solvent as well.

EXAMPLE XII 3-methyl-l2.3.4.10.l4b-hexahydro-pyrimidinol3.4- a ]dibenzo[c.f]azepine By the process described in example X] A l g of phosgene and 2.5 g of 6-methylaminoethyl-5.6- dihydro-l lH-dibenzo[b.e]-azepine are converted into 3-methyl-l .2.3.4. I 0. 4b-hexahydro-4-ketopyrimidino[3.4-a]dibenzo[c.fiazepine.

This substance is reduced with LiAlH. in tetrahydrofuran by the process described in example XI B.

Melting point fumarate: l92-l93C.

EXAMPLE Xlll 3-methyl-l .2.3.4. l 0. l 4b-hexahydro-pyrimidino[ 3.4- a ]dibenzo[c.f]azepine To 2.4 g of fi-methylaminoethyl-S.6-dihydro-l 1H- dibenzo[b.e]azepine (melting point: l24-l26C). dissolved in 50 ml of tetrahydrofuran. a solution of 2 g of N.N'-carbonyldiimidazol in 30 ml of tetrahydrofuran is added. while stirring. After 1.5 hours stirring at room temperature about ml of tetrahydrofuran are distilled off. after which the residue is diluted with water. Extraction of this mixture with benzene. washing of the extracts with water. drying on sodium sulphate and evaporation of the benzene solution gives 2.4 g of 3- methyl-] .2.3.4. I 0. l 4b-hexahydro-4-ketopyrimidinol3.4-a]dibenzo[c.f]azepine.

This substance is dissolved in ml of tetrahydrofur-an. after which a solution of 0.8 g of diboran in 50 ml of tetrahydrofuran is added. The mixture is heated in a sealed ampoule for 5 hours. at 45C. After that alcohol is added to the mixture. whereupon it is stirred for some time. After that the mixture is partly evaporated. then acidified with dilute acid (0.1 N HCl) and extracted with benzene.

The benzene extracts are processed in the conventional manner.

Melting point fumarate: l90l 92C.

EXAMPLE XIV a. Z-kcto-l.2.3.4.l().l4b-hexahydro-pyrimidino[3.4- a]dibenzo[c.f]azepine 10 g of 6-carboxamidomethyl-5.6 dihydromorphanthridine is dissolved in 300 ml ethanol (70%). after which H1O ml of a 37% formaldehyde solution in water is added. The mixture is refluxed for 6 hours. after which the solvent is substantially evaporated. The resi due obtained is filtered and the solid substance dried.

Melting point: l8ll85C. yield 85% Rf in ethyl-acetate ()3 on SiO b. l 2.3.4. l0.14b hexahydro-pyrimidinol3.4- a ]dibenzol c.f]azepine.HCl

S g of the compound obtained in a. is dissolved in 75 ml tetrahydrofurane (THF). The solution is gently added to a suspension of 4 g LiAlH. in I ml THF. The mixture is refluxed for 3 hours and after that cooled down to 0C. To this cooled mixture l6 ml water is gently added. whereupon the mixture is fil tered. The filtrate obtained is evaporated and the residual oil dissolved in HCl/EtOH. The solution is filtered and the solid substance obtained is dried.

Melting point HCl-salt: ll4Zl8C; yield 88%.

What is claimed is: l. A compound of the formula:

f; X r. il k. A.

in h J in which X is selected from the group consisting of oxygen.

sulfur. the group NR. and CH R. and R are selected from the group consisting of hydrogen. halogen. hydroxy. alkyl having [-6 carm bon atoms. alkoxy having l6 carbon atoms. and trifluoromethyl;

R is selected from the group consisting of hydrogen.

alkyl having 1-6 carbon atoms. and R. is selected from the group consisting of hydrogen 7S and alkyl having l-o carbon atoms. and the pharinaceutically acceptable acid addition salts and quaternary ammonium compounds thereof. 2. A compound according to claim I in which X is CH- 3. A compound according to claim 1 in which X is oxygen.

3,892,695 Dated July 1, 1975 Patent No.

) Willem Jacob Van Der Burg Page 1 Inventor(s It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Abstract, the formula should read as shown below:

Column 1, lines 55-65, the formula should read as shown below:

a x r *1 (R N-CQ 2 5 H FORM PO-1050 UsCOMM-Dc wan-p" u s GOVLRNMENT mzmnuc OFFICE 869. 93 O Patent No. 5, 92, 95 Dated ly 1, 1975 Willem Jacob Van Der Burg Page 2 Inventor(s) It is certified that error appears inthe above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, lines L|--8, the formula should read as shown below:

Column 2, lines l8-25,the formula should read as shown below:

I I'AQN (I?) 5 Column 3, after line 55, the formula should read as shown below:

9 to u a 0 N 13 5 14b 6 14 4 I ORM Po-1050 (10-69) USCOMM-DC 60376-P69 U 5 GOVERNMENT PRINTING OFFICE 5- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 5 9 a 695 Dated July 1 a 1975 OHS) Willem Jacob Van Der Burg Page 3 Invent It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 12, lines 5-12, Claim 1, the formula should read as shown below:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,892,695 Dated July 1, 1975 Willem Jacob Van Der Burg Page A Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns 5 and 6, lines 1 through A9 should read as shown 1 Z '3 l0, 1db-hoxahyd'?o-pyrimidino [L -d dibenzzoib,f}(1,4)diazepine.

' l 2 {3 4 10, 14b-hexahydro-pyrimidinc [3,4 -a] dibenzoc,f]azepine.

X O: 1l-aminoethyl-l0,ll-dihydrodibenzo[b,f](1,4)oxazepine X S: ll -aminoethyll0,1l-dihydrodibenzofbfi](1,4)thiazepine X N: ll--aminoethy1-10,ll-dihydro- 5H-dibenzo[b,e](1,4)diazepine.

6-aminoethyl-S,6-dihYc3ro-llH- dibenzo{b,e]azepine or B-amihoethyl-S,6-dihydro-morphan- H,N thridine Signal and Scaled this thirtieth Day of December 1975 [SEAL] Arrest:

RUTl-l C. MASON C. IAISIIALL DANN Arresting Officer Commission" 0! Damn: and Trademark: 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 in which X is -CH2-.
 3. A compound according to claim 1 in which X is oxygen. 